Ultraviolet B radiation (UVB) contains the shortest wavelengths of sunlight penetrating to the Earth's surface (290-320nm). These wavelengths are directly linked to skin cancer formation and immunological alterations leading to systemic immunosuppression in mammals. Experimental studies strongly link this suppression to skin cancer. Irradiation of the skin with UVB is systemically suppressive of contact hypersensitivity reactions (CHS) to chemicals, delayed type hypersensitivity responses (DTH) to hapten-conjugated cells, to viruses, and to parasites. UV irradiation also suppresses the DTH response to alloantigens, and has been shown to prolong experimental allograft acceptance. UV suppression prevents the immunologic rejection of highly antigenic UV tumors. We proposed that immune suppression of T-cell immunity is protective and evolved to prevent autoimmune attack against skin cells containing sunlight-induced "photoantigens". UV suppression provides time to synthesize new skin without the "photoantigens". This hypothesis predicts that too much sun exposure could lead to inadvertent protection of any pre-existing skin tumor cells as well. Our research has been aimed at understanding the mechanism by which UV radiation induces immunosuppression. Our most critical finding was that suppression of CHS was mediated by the presence, on the outermost layer of skin, of an unusual photoreceptor capable of initiating immune suppression. We identified this photoreceptor as urocanic acid (UCA), de-aminated histidine. In this proposal we expand our studies to include (i) the effects of UV radiation on cytokine induction and localization; cytokines are important immunoregulatory signals recently shown to be activated by UVB irradiation of skin; (2) studies to isolate and identify the cell receptor for cis UCA binding; experimental evidence indicates this to be the moiety which initiates immune suppression and to study the mechanism of antigen-presenting cell alteration by UV and cis UCA; (3) the effects of UVA radiation on UVB- induced immune suppression since UVA may modulate the expression of UVB- induced suppressor signals through the UVA-UVB ratio which changes throughout sunlight exposure; and (4) the effects of the amino acid L- histidine on skin cancer because of its ability to enhance immune suppression through cis UCA formation. Significance:UV-induced immune suppression has now been confirmed in humans and appears to be independent of pigmentation. In addition to skin cancer growth, the development of certain types of cell-mediated infectious diseases appear to be influenced by UV suppression. Recently published laboratory experiments indicate a potential role for UV-B,cis UCA in delaying the rejection of transplanted tissue. This opens up the possibility of using UCA as a therapeutic agent in delaying the rejection of transplanted organs and tissues. Finally, significant stratospheric ozone reduction has become a reality over populated areas of the Northern Hemisphere. We recently showed that the doses of UVB used experimentally to induce suppression can be achieved by natural sunlight exposure over most populated countries between 40 N and 40 S in summertime. Immune suppressing solar UVB irradiances may, therefore, be expected to increase by stratospheric ozone depletion over large populated areas of the world. Given the significant losses of ozone over the U.S. during summer 1993 (10-20%) this may have already occurred.